The broad objective of this application is to define the effect of atherosclerosis on the renal microcirculation and tubular function. Our working hypothesis is that during the evolution of atherosclerosis, renovascular endothelial dysfunction contributes to a reduction in intra-renal perfusion and alterations in tubular dynamics, which may eventuate in renal hemodynamic and functional damage, and may be demonstrable even during hypercholesterolemia as blunted microcirculatory and tubular responses to the endothelium-dependent vasodilator and diuretic agent acetylcholine. Moreover, this renal injury may be further aggravated with concurrent renal artery stenosis or hypertension, but may regress upon return to a normal diet We propose to use both electron-beam computed tomography (EBCT), a unique scanner capable of quantifying the function of the regional renal microcirculation and tubules in the in vivo, intact kidney, as well as in vitro techniques in isolated renal microvessels. Our specific aims are, hence, to determine in pigs regional renal perfusion and excretory function before, during, and subsequent to reversal versus continuation of hypercholesterolemia before and after administration of acetylcholine, and in vitro in isolated renal microvessels. Furthermore, to determine these parameters, with and without hypercholesterolemia, in pigs with a concurrent super-imposed renal artery stenosis, both in the stenosed kidney (exposed to low perfusion pressure) and in the contra-lateral kidney (exposed to high arterial pressure), and finally in normal pigs. The significance of this proposal is that may greatly advance our recognition and understanding of the mechanisms of renal damage during the evolution of atherosclerosis, and contribute to developing strategies to protect the kidney and cardiovascular system. The applicant is an Assistant Professor in the Department of Physiology at the Mayo Clinic, who plans to pursue a career as an independent investigator. The applicant's immediate objective is to become a well trained investigator capable of applying basic science techniques to study renal and cardiac physiology and pathophysiology in both animal and human models. The overall goal of the applicant's research is to use high-resolution, noninvasive methods to acquire data describing the in vivo cardiac and renal alterations and adaptive responses to cardiovascular disease in general and evolving atherosclerosis in particular, and furthermore, reliable data applicable for future clinical diagnostic and therapeutical use.